"To our knowledge, this is the first published evidence of a link between protein misfolding due to enzymatic machinery malfunction found in a number of degenerative diseases and free radical stress in nerve cells," said Stuart A. Lipton, M.D., Ph.D., Professor and Director of the Del E. Webb Center for Neurosciences and Aging at the Burnham Institute and senior author of the study. Dr. Lipton is also a clinical neurologist in La Jolla. "Our data demonstrate a previously unrecognized relationship between NO and protein misfolding in degenerative disorders, showing that PDI can be a target of NO in cellular models of Parkinson's disease and human neurodegenerative disease."
A protein's structure determines its function. Genetic defects as well as exposure to free radicals or possibly other types of cellular stress can cause small structural defects that lead to protein misfolding. If the misfolded proteins cannot be refolded properly or degraded, they may build up in the cell to cause dysfunction. Defects in either the protein folding or degradation pathways can lead to accumulation of misfolded proteins. The accumulation of misfolded proteins is a common pathogenic mechanism in many diseases, including neurodegenerative disorders.
In normal circumstances, PDI levels increase in response to accumulation of misfolded proteins due to cellular stress. PDI acts as a chaperone for aggregated proteins, rearranging their chemical bonds and thus refolding the proteins to function normally. The new research by Dr. Lipton and his colleagues shows that molecules related to the free radical NO, which is present in elevated levels in neurodegenerative diseases, attacks PDI via a chemical S-nitroyslation reaction, altering PDI's structure and blocking its normal neuroprotective function, which ultimately leads to nerve cell injury and even death. These new results also show that this altered form of PDI is present in elevated amounts in patients with Alzheimer's and Parkinson's Disease, indicating that it is a potential marker for the disease as well as a potential therapeutic target.
This article titled "S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration," is authored by Drs. Takashi Uehara, Tomohiro Nakamura, Dongdong Yao, Zhong-Qing Shi, and Zezong Gu (all in Dr. Lipton's laboratory), Yuliang Ma (in the Protein Analysis Facility at the Burnham), Eliezer Masliah (at UCSD), Yasuyuki Nomura (at Hokkaido University in Sapporo, Japan), and Dr. Lipton, the senior author. (Dr. Uehara recently joined the faculty of Hokkaido University.)
This research was supported by grants from the National Institutes of Health, the American Parkinson's Disease Association, San Diego Chapter, an Ellison Senior Scholars Award in Aging, the Mitsubishi Pharma Research Foundation, and a grant-in-aid from the Ministry of Education, Culture, Sports and Technology of Japan.
About the Burnham Institute for Medical Research
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